Rapid regulation of endoplasmic reticulum dynamics in dendritic spines by NMDA receptor activation.
Endoplasmic reticulum (ER) is motile within dendritic spines, but the mechanisms underlying its regulation are poorly understood. To address this issue, we have simultaneously imaged morphology and ER content of dendritic spines in cultured dissociated mouse hippocampal neurons. Over a 10 min period, spines were highly dynamic, with spines both increasing and decreasing in volume. ER was present in approximately 50% of spines and was also highly dynamic, with a net increase over this period of time. Inhibition of the endogenous activation of NMDA receptors resulted in a reduction in ER growth. Conversely, augmentation of the synaptic activation of NMDA receptors, by elimination of striatal-enriched protein tyrosine phosphatase (STEP), resulted in enhanced ER growth. Therefore, NMDA receptors rapidly regulate spine ER dynamics.


High-resolution phylogenetic analysis of hepatitis C virus adaptation and its relationship to disease progression.
Hepatitis C virus (HCV) persists in the majority of those infected despite host immune responses. Evidence has accrued that selectively fixed mutations in the envelope genes (E1 and E2) are associated with viral persistence, particularly those that occur within the first hypervariable region of E2 (HVR1). However, the individual amino acid residues under selection have not been identified, nor have their selection pressures been measured, despite the importance of this information for understanding disease pathogenesis and for vaccine design. We performed a high-resolution analysis of published gene sequence data from individuals undergoing acute HCV infection, employing two phylogenetic methods to determine site-specific selection pressures. Strikingly, we found a statistically significant association between the number of sites selected and disease outcome, with the fewest selected sites in fulminant HCV cases and the greatest number of selected sites in rapid progressors, reflecting the duration and intensity of the arms race between host and virus. Moreover, sites outside the HVR1 appear to play a major role in viral evolution and pathogenesis, although there was no association between viral persistence and specific mutations in E1 and E2. Our analysis therefore allows fine dissection of immune selection pressures, which may be more diverse than previously thought. Such analyses could play a similarly informative role in studies of other persistent virus infections, such as human immunodeficiency virus.


Transfemoral Approach for Intraoperative Angiography in the Prone or Three-quarter Prone Position : A Revisited Protocol for Intracranial Arteriovenous Malformation and Fistula Surgery.
Among the different arterial accesses, the femoral access is the main approach for intraoperative angiography (IOA) performed in a prone position. Without a standardized protocol, however, the application of prone IOAs in intracranial arteriovenous malformation (AVM) or arteriovenous fistula (AVF) surgery remains limited by its procedural complexity. This study describes the detailed protocol for prone IOA through a transfemoral approach and highlights several refinements in preparing this procedure. This study retrospectively reviewed the intracranial or high cervical AVM/AVF surgical cases in which both resection and IOA were performed in the prone or three-quarter prone position. Extended femoral sheath approaches and radiolucent head clamps were used in all cases. An aneurysm clip, serving as a localization landmark in IOA, was routinely placed within the surgical field. The IOA imaging, clinical impact of IOA, and complications related to the procedure were recorded. A total of six AVM and three AVF cases, operated on in the prone (n = 7) or three-quarter prone (n = 2) positions, were included. Multiple vessel injections were required in 66.7% of cases, and IOA was successfully performed in every intended vessel. All IOA images were adequate for interpretation, except for two cases in which the non-radiolucent component of the head clamp obscured the region of interest in the lateral views. Incomplete occlusion was identified in two patients, and the aneurysm clip provided precise guidance in localizing the residual nidus. Final IOA confirmed complete lesion removal in all cases, and there were no IOA-related complications. Three key steps in setting-up a prone IOA procedure for intracranial AVM/AVF surgery are proposed: (1) utilize an extended femoral sheath approach, (2) establish a localization landmark with an aneurysm clip and (3) avoid possible image interference from the non-radiolucent component of the head clamp.


Impacts of a smoking cessation benefit among employed populations.
The objective of this study was to project the health and economic impacts of providing a workplace smoking cessation benefit. The authors conducted an update of a previously published outcomes model using recently published data and clinical trial results. In four example workplace types evaluated, coverage of a cessation benefit resulted in greater numbers of successful cessations and decreased rates of smoking-related diseases. Total savings from benefit coverage (decreased healthcare and workplace costs) exceeded costs of the benefit within 4 years. Total savings per smoker ranged from 350 dollars to 582 dollars at 10 years and 1152 dollars to 1743 dollars at 20 years. Internal rate of return ranged from 39% to 60% at 10 years. Providing a workplace smoking cessation benefit results in substantial health and economic benefits with economic savings exceeding the cost of the benefit within a relatively short period. Providing a workplace smoking cessation benefit is projected to increase the rate of smoking cessation as well as decrease the incidence of smoking-related conditions and healthcare costs. In addition, workplace cessation benefits can result in decreased absenteeism, increased productivity, and net cost savings within 4 years.


Zebrafish embryo screen for mycobacterial genes involved in the initiation of granuloma formation reveals a newly identified ESX-1 component.
The hallmark of tuberculosis (TB) is the formation of granulomas, which are clusters of infected macrophages surrounded by additional macrophages, neutrophils and lymphocytes. Although it has long been thought that granulomas are beneficial for the host, there is evidence that mycobacteria also promote the formation of these structures. In this study, we aimed to identify new mycobacterial factors involved in the initial stages of granuloma formation. We exploited the zebrafish embryo Mycobacterium marinum infection model to study initiation of granuloma formation and developed an in vivo screen to select for random M. marinum mutants that were unable to induce granuloma formation efficiently. Upon screening 200 mutants, three mutants repeatedly initiated reduced granuloma formation. One of the mutants was found to be defective in the espL gene, which is located in the ESX-1 cluster. The ESX-1 cluster is disrupted in the Mycobacterium bovis BCG vaccine strain and encodes a specialized secretion system known to be important for granuloma formation and virulence. Although espL has not been implicated in protein secretion before, we observed a strong effect on the secretion of the ESX-1 substrates ESAT-6 and EspE. We conclude that our zebrafish embryo M. marinum screen is a useful tool to identify mycobacterial genes involved in the initial stages of granuloma formation and that we have identified a new component of the ESX-1 secretion system. We are confident that our approach will contribute to the knowledge of mycobacterial virulence and could be helpful for the development of new TB vaccines.


Plasticity in the mediodorsal thalamo-prefrontal cortical transmission in behaving mice.
We studied changes in thalamo-prefrontal cortical transmission in behaving mice following both low-frequency stimulation of the mediodorsal thalamus (MD) and during extinction of a conditioned fear response. Electrical stimulation of the MD induces a field potential in the medial prefrontal cortex (mPFC) characterized by two initial negative-positive complexes (N1-P1 and N2-P2) followed by two positive-negative complexes (P2-N3 and P3-N4). The N1-P1 and N2-P2 complexes were identified as resulting from orthodromic and antidromic prefrontal activation, respectively. Because the two complexes were not often easily dissociated, plasticity in the prefrontal synaptic transmission was considered to result from changes in N1-P2 amplitude. Low-frequency thalamic stimulation (1, 200 pulses at 2 Hz) produced either long-term (at least 32 min) depression or potentiation of the N1-P2 amplitude. Mice submitted to fear conditioning (tone-shock association), displayed on the first day of extinction (tone-alone presentations) a strong freezing behavior, which decreased progressively, but was still high the following day. Extinction of conditioned fear was accompanied the first day by a depression of prefrontal transmission, which was converted into potentiation the following day. Potentiation of prefrontal transmission lasted at least 24 h following the second day of the fear extinction procedure. In conclusion, low-frequency thalamic stimulation can produce, in behaving mice, either depression or potentiation of prefrontal synaptic transmission. Decrease in prefrontal synaptic transmission observed during the first day of extinction may reflect processing of the high degree of predictiveness of danger (unconditioned stimulus: US) by the aversive conditioned stimulus (CS). However, the subsequent potentiation of transmission in the mPFC may be related to processing of cognitive information such as the CS will no longer be followed by the US, even if emotional response (freezing) to the CS is still high.


Limitations of the use of vacuum photodiodes in instruments for the measurement of laser power and energy.
The effect of the variation in the area sensitivity upon the calibration of instruments incorporating biplanar vacuum photodiodes for the measurement of laser power and energy is discussed. A technique for the measurement of the area sensitivity is described, and the experimental results for several tubes are given. At the present time it would appear to be difficult to use biplanar vacuum phctodiodes in devices to measure laser energy or power.


Lithium modulates striatal reward anticipation and prediction error coding in healthy volunteers.
Lithium is one of the most effective mood-stabilizing medications in bipolar disorder. This study was designed to test whether lithium administration may stabilize mood via effects on reward processing. It was hypothesized that lithium administration would modulate reward processing in the striatum and affect both anticipation and outcome computations. Thirty-seven healthy human participants (18 males, 33 with suitable fMRI data) received 11 (±1) days of lithium carbonate or placebo intervention (double-blind), after which they completed the monetary incentive delay task while fMRI data were collected. The monetary incentive delay task is a robust task with excellent test-retest reliability and is well suited to investigate different phases of reward processing within the caudate and nucleus accumbens. To test for correlations with prediction error signals a Rescorla-Wagner reinforcement-learning model was applied. Lithium administration enhanced activity in the caudate during reward anticipation compared to placebo. In contrast, lithium administration reduced caudate and nucleus accumbens activity during reward outcome. This latter effect seems related to learning as reward prediction errors showed a positive correlation with caudate and nucleus accumbens activity during placebo, which was absent after lithium administration. Lithium differentially modulates the anticipation relative to the learning of rewards. This suggests that lithium might reverse dampened reward anticipation while reducing overactive reward updating in patients with bipolar disorder. This specific effect of lithium suggests that a targeted modulation of reward learning may be a viable approach for novel interventions in bipolar disorder.


Optical tuning of silicon photonic structures with nematic liquid crystal claddings.
An analysis of and experimental demonstration of active optical tuning of silicon strip waveguides with methyl red doped nematic liquid crystal claddings is presented. Under low-power irradiation by polarized light, the reorientation of the nematic, the resulting index change, and phase shift produce a tuning range of 5.6 nm for the microresonator resonances.


The influence of dose rate on the induction of chromosome aberrations and gene mutation after exposure of plateau phase V79-4 cells with high-LET alpha particles.
While protracting exposures of low-LET radiations usually leads to a reduction in their effectiveness for a given dose, for high-LET radiation there is now substantial evidence for what has been called an inverse dose-rate effect, where under certain circumstances there is an increase in carcinogenesis or other biological effects, with decreasing dose rate. This study investigates the influence of dose rate on the induction of chromosome aberrations and gene mutations after irradiation of plateau phase V79-4 cells with high-LET alpha particles. The induction of chromosomal aberrations exhibited a linear relationship with dose and showed evidence of a small but significant conventional dose-rate dependence, with low-dose-rate exposures (0.28 Gy h(-1)) being less effective by about 20% (ratio 0.82 ± 0.04) compared to acute exposures. However no significant dose-rate effect was observed for cell survival or the induction of mutations in the HPRT gene for low-dose-rate exposure (8.0 × 10(-5) and 1.5 × 10(-2) Gy h(-1) for exposure of 0.36 and 0.69 Gy, respectively) when compared to acute exposures.


Mechanisms of hypertension and kidney disease in obesity.
Abnormal kidney function is an important cause as well as a consequence of obesity. Excess renal sodium reabsorption, probably in the loop of Henle, and a hypertensive shift of pressure natriuresis play a major role in initiating increased blood pressure associated with weight gain. The mechanisms responsible for increased sodium reabsorption and altered pressure natriuresis in obesity include activation of the renin-angiotension and sympathetic nervous systems, and physical compression of the kidneys due to accumulation of intrarenal fat and extracellular matrix. Sympathetic activation may be mediated, in part, by elevated circulating leptin and interactions with neuropeptides in the hypothalamus. Renal remodeling and extracellular matrix proliferation likely involve complex interactions between intrarenal physical forces, neurohumoral factors, and local growth factors and cytokines. Although glomerular hyperfiltration and increased arterial pressure help to compensate for increased renal tubular reabsorption in the early phases of obesity, these changes also increase glomerular capillary wall stress which, along with activation of neurohumoral systems and increased lipids and glucose intolerance, cause glomerular cell proliferation, matrix accumulation, and eventually glomerulosclerosis and loss of nephron function in the early phases of obesity. This creates a slowly developing vicious cycle that requires additional increases in arterial pressure to maintain sodium balance and therefore makes effective antihypertensive therapy more difficult. Because obesity is the main cause of Type 2 diabetes and an important cause of human essential hypertension, it seems likely that obesity is also one of the most important risk factors for end-stage renal disease.


Accommodating Conscientious Objection in Medicine-Private Ideological Convictions Must Not Trump Professional Obligations.
The opinion of the American Medical Association (AMA) Council on Ethical and Judicial Affairs (CEJA) on the accommodation of conscientious objectors among medical doctors aims to balance fairly patients' rights of access to care and accommodating doctors' deeply held personal beliefs. Like similar documents, it fails. Patients will not find it persuasive, and neither should they. The lines drawn aim at a reasonable compromise between positions that are not amenable to compromise. They are also largely arbitrary. This article explains why that is the case. The view that conscientious objection accommodation has no place in modern medicine is defended.


Inhibition of the Histone Methyltransferase EZH2 Enhances Protumor Monocyte Recruitment in Human Mesothelioma Spheroids.
Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with a long latency period and dismal prognosis. Recently, tazemetostat (EPZ-6438), an inhibitor of the histone methyltransferase EZH2, has entered clinical trials due to the antiproliferative effects reported on MPM cells. However, the direct and indirect effects of epigenetic reprogramming on the tumor microenvironment are hitherto unexplored. To investigate the impact of tumor-associated macrophages (TAMs) on MPM cell responsiveness to tazemetostat, we developed a three-dimensional MPM spheroid model that recapitulates in vitro, both monocytes' recruitment in tumors and their functional differentiation toward a TAM-like phenotype (Mo-TAMs). Along with an increased expression of genes for monocyte chemoattractants, inhibitory immune checkpoints, immunosuppressive and M2-like molecules, Mo-TAMs promote tumor cell proliferation and spreading. Prolonged treatment of MPM spheroids with tazemetostat enhances both the recruitment of Mo-TAMs and the expression of their protumor phenotype. Therefore, Mo-TAMs profoundly suppress the antiproliferative effects due to EZH2 inhibition in MPM cells. Overall, our findings indicate that TAMs are a driving force for MPM growth, progression, and resistance to tazemetostat; therefore, strategies of TAM depletion might be evaluated to improve the therapeutic efficacy of pharmacological inhibition of EZH2.


Segmentation of images of abdominal organs.
Abdominal organ segmentation, which is, the delineation of organ areas in the abdomen, plays an important role in the process of radiological evaluation. Attempts to automate segmentation of abdominal organs will aid radiologists who are required to view thousands of images daily. This review outlines the current state-of-the-art semi-automated and automated methods used to segment abdominal organ regions from computed tomography (CT), magnetic resonance imaging (MEI), and ultrasound images. Segmentation methods generally fall into three categories: pixel based, region based and boundary tracing. While pixel-based methods classify each individual pixel, region-based methods identify regions with similar properties. Boundary tracing is accomplished by a model of the image boundary. This paper evaluates the effectiveness of the above algorithms with an emphasis on their advantages and disadvantages for abdominal organ segmentation. Several evaluation metrics that compare machine-based segmentation with that of an expert (radiologist) are identified and examined. Finally, features based on intensity as well as the texture of a small region around a pixel are explored. This review concludes with a discussion of possible future trends for abdominal organ segmentation.


Fluoride augments the mitogenic and antigenic response of human blood lymphocytes in vitro.
It has been shown that fluoride, the agent responsible for reduction of dental caries worldwide and a recognized proliferative agent, is an adjuvant when given intragastrically to rats. Furthermore, plasma fluoride levels increase in humans after various fluoride treatments. The studies presented here show that fluoride also has the ability to affect the cells of the human immune system. This was tested by measuring the effect of sodium fluoride (NaF) on cytokine production by human whole blood cells stimulated in vitro. These studies revealed that NaF augments the human lymphocyte response from human blood to a mitogen (phytohemagglutinin, PHA) or a specific antigen (morbilli antigen from infected cells, MorbAg). The cytokine interferon-gamma (IFN-gamma), released from activated T and/or NK cells, was significantly (p<0.01) increased when whole blood cells were simultaneously incubated with 0.62 mmol/l NaF and PHA compared to PHA alone. This tendency was also true for NaF and MorbAg. The lymphocyte activation marker interleukin-2 receptor (measured in soluble form) increased after simultaneous stimulation of the cells with PHA and 0.62 mmol/l NaF compared to stimulation with PHA only. However, 0.62 mmol/l NaF did not enhance interleukin-6 release, in blood mainly produced by monocytes. The ability to influence the IFN-gamma release during an immune response could be one of the primary means by which the fluoride ion influences the immune system.


Optimal filter design for shielded and unshielded ambient noise reduction in fetal magnetocardiography.
The greatest impediment to extracting high-quality fetal signals from fetal magnetocardiography (fMCG) is environmental magnetic noise, which may have peak-to-peak intensity comparable to fetal QRS amplitude. Being an unstructured Gaussian signal with large disturbances at specific frequencies, ambient field noise can be reduced with hardware-based approaches and/or with software algorithms that digitally filter magnetocardiographic recordings. At present, no systematic evaluation of filters' performances on shielded and unshielded fMCG is available. We designed high-pass and low-pass Chebychev II-type filters with zero-phase and stable impulse response; the most commonly used band-pass filters were implemented combining high-pass and low-pass filters. The achieved ambient noise reduction in shielded and unshielded recordings was quantified, and the corresponding signal-to-noise ratio (SNR) and signal-to-distortion ratio (SDR) of the retrieved fetal signals was evaluated. The study regarded 66 fMCG datasets at different gestational ages (22-37 weeks). Since the spectral structures of shielded and unshielded magnetic noise were very similar, we concluded that the same filter setting might be applied to both conditions. Band-pass filters (1.0-100 Hz) and (2.0-100 Hz) provided the best combinations of fetal signal detection rates, SNR and SDR; however, the former should be preferred in the case of arrhythmic fetuses, which might present spectral components below 2 Hz.


Aortoiliac occlusive disease in patients with known or suspected peripheral vascular disease: safety and efficacy of gadofosveset-enhanced MR angiography--multicenter comparative phase III study.
To prospectively determine the safety and efficacy of the gadolinium-based blood pool magnetic resonance (MR) imaging contrast agent gadofosveset in patients known to have or suspected of having peripheral vascular disease. Ethical committee approval and patient written informed consent were obtained. This study was compliant with the Health Insurance Portability and Accountability Act. Adults known or suspected to have peripheral vascular disease received gadofosveset (0.03 mmol per kilogram of body weight) for MR angiography of the aortoiliac region. Gadofosveset-enhanced MR angiography and unenhanced two-dimensional time-of-flight MR angiography were compared with the reference standard, conventional angiography, for the presence of vascular stenosis. All patients were monitored for adverse events with hematologic analysis, analysis of blood chemistry, urinalysis, and electrocardiographic parameters; these methods were analyzed to determine safety. A total of 274 patients were enrolled at 37 centers. Gadofosveset-enhanced MR angiography showed significant improvement (P < .001) compared with unenhanced MR angiography for each of the readers for diagnosis of clinically significant (> or = 50%) stenosis. Specificity and accuracy were significantly greater for three readers, and sensitivity increased significantly for two readers. For all readers, the area under the receiver operator characteristic curve for both quantitative and qualitative measures of significant disease increased (P < .001) for gadofosveset-enhanced MR angiography versus two-dimensional time-of-flight MR angiography. All readers also expressed more confidence in diagnosis (P < .001) and found fewer images to be uninterpretable (0.5% vs 11.0%). The most common adverse events were as follows: feeling hot, 12 (4.4%) patients; nausea, 10 (3.6%) patients; headache, nine (3.3%) patients; and burning sensation, eight (2.9%) patients. Only four serious adverse events were reported, in three patients, and all events were rated as unlikely related to the drug. No patients were excluded because of adverse events or laboratory abnormalities. There were no clinically important trends in the findings of hematologic analysis, blood chemistry, urinalysis, electrocardiography, or physical examination. On the basis of substantial improvements over non-contrast MR angiography in efficacy and a minimal and transient side-effect profile, gadofosveset was found to be safe and effective for MR angiography in patients known or suspected to have peripheral vascular disease.


The effect of parental rearing conditions on offspring life history in Anopheles stephensi.
The environmental conditions experienced by parents are increasingly recognized to impact the success of offspring. Little is known on the presence of such parental effects in Anopheles. If present, parental effects could influence mosquito breeding programmes, some malaria control measures and have epidemiological and evolutionary consequences. The presence of parental effects on offspring emergence time, size, survival, blood meal size and fecundity in laboratory reared An. stephensi were tested. Parental rearing conditions did not influence the time taken for offspring to emerge, or their size or survival as adults. However, parental effects were influential in determining the fecundity of daughters. Counter-intuitively, daughters of parents reared in low food conditions produced larger egg clutches than daughters of parents reared in high food conditions. Offspring reared in low food conditions took larger blood meals if their parents had also experienced a low food environment. So far as we are aware, this is the first evidence of parental effects on progeny in Anopheles.


Diagnosis of congenital and adult-onset hypothyroidism in cats.
Whereas hyperthyroidism is the most common endocrine disorder in the cat, hypothyroidism is the least common feline endocrine disorder. This is a the result of several factors including low index of suspicion, rarity of the naturally occurring hypothyroidism in cats, and a lack of species specific tests for endogenous TSH and antithyroglobulin antibodies. Nonetheless, hypothyroidism does occur in cats, especially in kittens and after radioactive treatment for hyperthyroidism. The clinician should become familiar with the common presentations of congenital and adult-onset hypothyroidism in cats. In addition, some of the tests specific to dogs (such as endogenous canine TSH) may be utilized to diagnose subclinical hypothyroidism in cats. Fortunately, the treatment of feline hypothyroidism with synthetic levothyroxine is both straightforward and effective.


Long-period grating refractive index sensor with a modified cladding structure for large operational range and high sensitivity.
What is believed to be a novel long-period grating (LPG) refractive index sensor with a modified cladding structure is proposed and studied. In the proposed structure, the cladding of the fiber has a two-layer structure, i.e., a cladding layer of low refractive index with a reduced radius and an overlay of high refractive index. The sensitivity of the structure-modified LPG sensor to the ambient refractive index change as a function of the cladding layer and overlay parameters is investigated by way of modeling. It is found that an increase of the ambient refractive index causes a field redistribution of the cladding mode into the overlay when the parameters of the overlay are properly selected. It is shown that by reducing the radius of the cladding layer, the operational range of the LPG refractive index sensor can be as large as 0.195 (from 1.244 to 1.440) with a minimum sensitivity of 660 nm/refractive index, which represents a 31% increase of operational range in comparison with the operational range obtained from the reported structure. The design guidelines for achieving this large operation range and high sensitivity are explained by investigating the dependence of the cladding modes on the radius of the cladding layer.


Does foot placement affect the reliability of static foot posture measurements?
Previous studies have reported conflicting results on whether different foot placements in standing can affect static measurements of foot posture. We sought to determine whether three measurements of static foot posture could be consistently measured in three different foot placements while standing. Twenty individuals, 12 women and eight men, with a mean age of 24.8 years consented to participate. Two raters assessed the dorsal arch height, midfoot width, and heel width of each foot while the participant stood in the following three foot placements: a standardized placement, a participant-determined placement after marching in place, and a rater-determined foot placement based on observation of the participant's angle of gait and base of support while walking. All three measurements of static foot posture were shown to have high levels of intrarater and interrater reliability. Significant differences in the measurements of dorsal arch height, midfoot width, and heel width were found among all three of the foot placements. There were no differences between the two raters for any of the three measurements of foot posture. Based on these findings, we recommend that clinicians perform measurements of static foot posture using the same standing foot placement between sessions to ensure a high level of measurement consistency.


ALBINO3, an Arabidopsis nuclear gene essential for chloroplast differentiation, encodes a chloroplast protein that shows homology to proteins present in bacterial membranes and yeast mitochondria.
The albino3 (alb3) mutant of Arabidopsis forms white or light yellow cotyledons and leaves and when germinated on soil does not survive beyond the seedling stage. The chloroplasts of the mutant are abnormal, as determined by electron microscopy, and contain reduced levels of chlorophyll. However, the chloroplasts of alb3 mutants are sufficiently differentiated to enable the expression of two nuclear genes whose transcription requires the presence of chloroplasts. The ALB3 gene was isolated by transposon tagging with the Activator/Dissociation transposable element system. ALB3 is a novel plant gene whose product shows homology to a bacterial membrane protein previously identified in five bacterial species and to a yeast protein, OXA1, and its human homolog. OXA1 is required in the mitochondria for proper assembly of the cytochrome oxidase complex. ALB3 does not have a function identical to OXA1 because mitochondrial cytochrome oxidase activity is not affected in the mutant, and immunogold labeling as well as chloroplast import experiments performed in vitro demonstrated that the ALB3 protein is present in chloroplast membranes. ALB3 might have a function related to that of OXA1 and be involved in the assembly of a chloroplast enzyme complex.


Incidence of spontaneous intracerebral hemorrhage among Hispanics and non-Hispanic whites in New Mexico.
To compare the incidence of spontaneous intracerebral hemorrhage (ICH) among Hispanics and non-Hispanic whites living in Bernalillo County, NM. There are differences in cerebrovascular disease incidence between racial and ethnic groups. Knowing these differences is likely to optimize stroke prevention and evaluation. Medical records review of all possible cases of ICH occurring between January 1, 1993 and December 31, 1993 among residents of Bernalillo County, NM, in all local hospitals. Hospital records were identified by ICD-9-CM codes. Also, State Medical Examiner records review for additional ICH cases occurring during the same time interval. The 1990 U.S. census provided the population base. There were 47 spontaneous ICHs among 267,965 non-Hispanic whites and 39 spontaneous ICHs among 178,310 Hispanics. Incidence of ICH rises exponentially with age in both groups. The age- and sex-adjusted total annual incidence of ICH per 100,000 people is 16.6 among non-Hispanic whites and 34.9 among Hispanics (relative risk for Hispanics 2.10, 95% confidence interval 1.35 to 3.26, p = 0.001). The age-adjusted incidence rates among men and women are not significantly different in either ethnic group. The incidence of spontaneous ICH among Hispanic residents of Bernalillo County, NM, is approximately twice that among non-Hispanic whites. The reasons for this difference require further investigation.


Acute neurobehavioral effects of toluene: involvement of dopamine and NMDA receptors.
Toluene, a widely used and commonly abused organic solvent, causes a variety of behavioral disturbances in both humans and animals. In this study, the effects of toluene on locomotor activity, motor coordination, and passive avoidance learning, along with the possible mechanism underlying these toluene-induced behavioral manifestations, were investigated. Sprague-Dawley rats were tested in the open field test, rotarod test, and step-through avoidance learning task after receiving toluene (250-750 mg/kg, i.p.). Toluene dose-dependently produced locomotor hyperactivity, motor incoordination, and memory impairment. In order to determine the possible roles of dopamine and NMDA receptors in these behavioral responses to toluene, dopamine D1 receptor antagonist SCH23390, D2 receptor antagonist raclopride, D3 receptor antagonist nafadotride, or d-serine, a co-agonist at the glycine binding site of NMDA receptors, were given prior to toluene administration. SCH23390, raclopride, and nafadotride attenuated locomotor hyperactivity, but not motor incoordination and memory impairment in response to toluene, whereas d-serine reduced all the toluene-induced behavioral alterations. These findings suggest that blockade of NMDA receptors may play a critical role in acute toluene-induced locomotor hyperactivity, motor incoordination, and memory impairment, and that dopamine neurotransmission may be specifically involved in locomotor hyperactivity.


Optimizing Special Operations Forces Operator Talents and Mission Capabilities: Human Performance Optimization and Total Force Fitness Capability-Based Blueprint and Targeting System.
The Special Operations Forces (SOF) community represents an impressive degree of diversity in talents, culture, mission essential tasks, and occupational risk exposures across Service branches, their career fields, and units. Sustaining the capabilities of the SOF Operator across a career lifespan requires collaboratively addressing the current gap between medical readiness and mission readiness with support services and their SOF end users. Given the diverse needs of SOF Operators and their units, realigning performance and health (P&H) service delivery to meet their specific needs will require the adoption of an alternative business framework, operationally focused metrics, and retargeting to ensure SOF Operators are not just medically ready, but mission ready. With restructuring of P&H service delivery occurring across the Department of Defense at all levels to support the 2018 National Defense Strategy, there is a greater need for collaborative synchronization, targeting, and validating operational return on investment with SOF Operators and SOF stakeholders. Here, we present the Human Performance Optimization (HPO) and Total Force Fitness (TFF) Capabilities-Based Blueprint (CBB) and Targeting System as an initial step to realigning service delivery. We examine the use of CBB as a translational tool to bridge the divide between P&H services and SOF Operator communities, and demonstrate how the CBB has significant applications to help construct appropriate programming and program evaluation, align resources and needs, and provide culturally appropriate services that should sustainably preserve SOF Operators' unique capabilities and their mission.


Big data, smart homes and ambient assisted living.
To discuss how current research in the area of smart homes and ambient assisted living will be influenced by the use of big data. A scoping review of literature published in scientific journals and conference proceedings was performed, focusing on smart homes, ambient assisted living and big data over the years 2011-2014. The health and social care market has lagged behind other markets when it comes to the introduction of innovative IT solutions and the market faces a number of challenges as the use of big data will increase. First, there is a need for a sustainable and trustful information chain where the needed information can be transferred from all producers to all consumers in a structured way. Second, there is a need for big data strategies and policies to manage the new situation where information is handled and transferred independently of the place of the expertise. Finally, there is a possibility to develop new and innovative business models for a market that supports cloud computing, social media, crowdsourcing etc. The interdisciplinary area of big data, smart homes and ambient assisted living is no longer only of interest for IT developers, it is also of interest for decision makers as customers make more informed choices among today's services. In the future it will be of importance to make information usable for managers and improve decision making, tailor smart home services based on big data, develop new business models, increase competition and identify policies to ensure privacy, security and liability.


Risk of Bleeding and Thrombosis in Patients 70 Years or Older Using Vitamin K Antagonists.
Previous studies have shown that, despite the higher risk of bleeding, the elderly still benefit from taking anticoagulants if they have a stringent indication. However, owing to the relatively low number of patients older than 90 years in these studies, it is unknown whether this benefit is also seen with the eldest patients. To determine how the risk of bleeding and thrombosis is associated with age in patients older than 70 years who were treated with a vitamin K antagonist (VKA). A matched cohort study was conducted of patients at a thrombosis service who were treated with a VKA between January 21, 2009, and June 30, 2012. All 1109 patients 90 years or older who were treated with a VKA were randomly matched 1:1:1 with 1100 patients aged 80 to 89 years and 1104 patients aged 70 to 79 years based on duration of VKA treatment. Data analysis was conducted from April 2015 to April 2016. The primary outcome was a composite of clinically relevant nonmajor and major bleeding. Secondary outcomes included thromboses and quality of VKA control. During 6419 observation-years, 713 of the 3313 patients (1394 men and 1919 women) had 1050 bleeding events. The risk of bleeding was not significantly increased in patients aged 80 to 89 years (event rate per 100 patient-years [ER], 16.7; hazard ratio [HR], 1.07; 95% CI, 0.89-1.27) and mildly increased in patients 90 years or older (ER, 18.1; HR, 1.26; 95% CI, 1.05-1.50) compared with patients aged 70 to 79 years (ER, 14.8). The point estimates for major bleeding (including fatal) were comparable for patients aged 80 to 89 years (ER, 1.0; HR, 1.09; 95% CI, 0.60-1.98) and those 90 years or older (ER, 1.1; HR, 1.20; 95% CI, 0.65-2.22) compared with those aged 70 to 79 years (ER, 0.9). The increase in bleeding risk was sharper in men than in women. Eighty-five patients (2.6%) developed a thrombotic event. Risk of thrombosis was higher for patients in their 90s (HR, 2.14; 95% CI, 1.22-3.75) and 80s (HR, 1.75; 95% CI, 1.002-3.05) than for patients in their 70s. Vitamin K antagonist control became significantly poorer with rising age, which partly explained the increased bleeding risk in patients 90 years or older, but most of the increased risk of thrombosis was not mediated by VKA control. These clinical practice data of patients considered eligible for anticoagulation show that the bleeding risk with a VKA only mildly increases after the age of 80 years, while there is a sharp increase in the risk of thrombosis in the same age group.


Cerebral microbleeds and quality of life in acute ischemic stroke.
This study evaluated the impact of cerebral microbleeds (CMBs) on the health-related quality of life (HRQoL) in 458 Chinese patients with first or recurrent acute ischemic stroke. HRQoL was assessed with the Short Form-36 (SF-36). Univariate analysis showed the presence of lobar CMBs to be negatively correlated with patients' physical functioning (PF; p < 0.01), social function (SF; p < 0.01), and role-emotional (RE; p < 0.05) scores. Subsequent linear regression analysis revealed lobar CMBs to be independently associated with the PF and SF scores (p < 0.05). The limitations of this study include the exclusion of patients with more severe stroke, the lack of longitudinal assessments, the use of a generic rather than stroke-specific HRQoL scale, and the less than optimal sensitivity of the CMB measurement. The study findings suggest that CMBs have a significant impact on the HRQoL of stroke survivors.


Epidemiology of culture-confirmed infections of Streptococcus pneumoniae (2012-2015) and nasopharyngeal carriage in children and households in Taiwan (2014-2015).
An observational study was performed to investigate the carriage rate and serotypes of Streptococcus pneumoniae in the 13-valent pneumococcal conjugate vaccine (PCV13) era in Taiwan. From March 2014 to March 2015 a total of 500 healthy children and their households (631 adults) were enrolled from two large medical centres for nasopharyngeal carriage survey. Clinical isolates were prospectively collected from June 2012 to May 2015 at Chang Gung Memorial Hospital. We applied a multiplex polymerase chain reaction in addition to culture to detect S. pneumoniae. S. pneumoniae was isolated from 12.0 % of the children and 3.6 % of the households. In the children's cohort only 23.3 % of the isolates could be assigned to PCV13 serotypes; non-vaccine serotypes were predominant (76.6 %) and the most frequently detected non-vaccine serotypes were 15A/F and 15B/C (both 13.3 %), followed by 23A (6.7 %). In the household cohort, 21.7 % belonged to PCV13 serotypes, and 78.3 % to non-vaccine serotypes. Clinical analysis of culture-confirmed pneumococcal infection showed that infection caused by PCV13 serotypes decreased by 47 % from 83 % in 2012-2013 to 44 % in 2014-2015, while infection caused by non-PCV13 serotypes increased from 17 to 56 %. Among the carriage isolates a significantly higher percentage belonged to serogroup 15 compared to serogroup 19 (26.6 vs 6.66 %, 2014-2015; P=0.003). Therefore, clinical isolates belonging to serogroup 15 were more prevalent than those belonging to serogroup 19 (44.1 vs 32.3 %, 2014-2015; P=0.318). The isolation of non-vaccine serotypes and unknown serotypes after the introduction of PCV13 in children highlights the importance of continued surveillance for emerging serotypes.


In situ manipulation and switching of dislocations in bilayer graphene.
Topological defects in crystalline solids are of fundamental interest in physics and materials science because they can radically alter the properties of virtually any material. Of particular importance are line defects, known as dislocations, which are the main carriers of plasticity and have a tremendous effect on electronic and optical properties. Understanding and controlling the occurrence and behavior of those defects have been of major and ongoing interest since their discovery in the 1930s. This interest was renewed with the advent of two-dimensional materials in which a single topological defect can alter the functionality of the whole system and even create new physical phenomena. We present an experimental approach to directly manipulate dislocations in situ on the nanometer scale by using a dedicated scanning electron microscope setup. With this approach, key fundamental characteristics such as line tension, defect interaction, and node formation have been studied. A novel switching reaction, based on the recombination of dislocation lines, was found, which paves the way for the concept of switches made of a bimodal topological defect configuration.


Draft Genomes of Symbiotic Frankia Strains AgB32 and AgKG'84/4 from Root Nodules of Alnus Glutinosa growing under Contrasted Environmental Conditions.
The genomes of two nitrogen-fixing Frankia strains, AgB32 and AgKG'84/4, were isolated from spore-containing (spore+) and spore-free (spore-) root nodules of Alnus glutinosa, but they did not sporulate upon reinfection. The two strains are described as representatives of two novel candidate species. Phylogenomic and ANI analyses indicate that each strain represents a novel species within cluster 1, with genome sizes of 6.3 and 6.7 Mb smaller than or similar to those of other cultivated Alnus-infective cluster 1 strains. Genes essential for nitrogen-fixation, clusters of orthologous genes, secondary metabolite clusters and transcriptional regulators analyzed by comparative genomic analyses were typical of those from Alnus-infective cluster 1 cultivated strains in both genomes. Compared to other cultivated Alnus-infective strains with large genomes, those of AgB32 and AgKG'84/4 had lost 380 or 409 genes, among which one hup cluster, one shc gene and the gvp cluster, which indicates genome erosion is taking place in these two strains.


Efficacy and safety of acetaminophen in the treatment of migraine: results of a randomized, double-blind, placebo-controlled, population-based study.
Although most persons with migraine treat their headaches with over-the-counter medication, systematic data on the safety and efficacy of widely used treatment, including acetaminophen, are sparse. This is a randomized, double-blind, placebo-controlled study comparing oral acetaminophen, 1000 mg (two 500-mg Extra Strength Tylenol tablets), with identical placebo in the treatment of a single acute migraine attack. Eligible subjects met International Headache Society diagnostic criteria for migraine with or without aura. Patients who usually required bed rest with their headaches or who vomited more than 20% of the time were excluded. The percentage of subjects who, at 2 hours after dosing, experienced a change in baseline pain intensity from severe or moderate pain to mild or no pain (headache response); and pain intensity difference from baseline at the 2-hour postmedication assessment. The headache response rate 2 hours after dosing was 57.8% in the acetaminophen group and 38.7% in the placebo group (P =.002). Pain-free rates at 2 hours were 22.4% in the acetaminophen group and 11.3% in the placebo group (P =.01). The mean pain intensity difference from baseline 2 hours after dosing was 1.08 in the acetaminophen group and 0.73 in the placebo group (P<.001). At 2 hours, other migraine headache characteristics, such as functional disability (P =.002), photophobia (P =.02), and phonophobia (P =.08), were significantly improved after treatment with acetaminophen vs placebo. Acetaminophen was highly effective for treating pain, functional disability, photophobia, and phonophobia in a population-based sample of persons with migraine, excluding the most disabled persons with migraine. The drug also had an excellent safety profile and was well tolerated. Arch Intern Med. 2000;160:3486-3492.


Zyxin is a novel interacting partner for SIRT1.
SIRT1 is a mammalian homologue of NAD+-dependent deacetylase sirtuin family. It regulates longevity in several model organisms and is involved with cell survival, differentiation, metabolism among other processes in mammalian cells. SIRT1 modulates functions of various key targets via deacetylation. Recent studies have revealed SIRT1 protects neurons from axonal degeneration or neurodegeneration. Further, SIRT1 null mice exhibit growth retardation and developmental defects, suggesting its critical roles in neurons and development. To identify novel binding partners for SIRT1 in the central nervous system, we performed yeast two-hybrid screening on human fetal brain cDNA library and found that zyxin is a possible binding partner. SIRT1 and zyxin transcript were both preferentially expressed in developmental mouse brain. Zyxin accumulates in the nucleus where it is co-localized with SIRT1 after treatment with leptomycin B in COS-7 cells. Furthermore, SIRT1 deacetylates zyxin, suggesting SIRT1 could interact with nuclear-accumulated zyxin and modulate its function through deacetylation. Zyxin could be a novel interacting partner of SIRT1. Zyxin is an adaptor protein at focal adhesion plaque, regulating cytoskeletal dynamics and signal transduction to convey signal from the ECM (extracellular matrix) to the nucleus. Our results raise the possibility that SIRT1 regulates signal transmission from ECM to the nucleus by modulating the functions of zyxin via deacetylation.


The Effect of Compression Socks on Maximal Exercise Performance and Recovery in Insufficiently Active Adults.
In athletic populations, compression socks (CS) may improve exercise performance recovery. However, their potential to improve performance and/or recovery following exercise in non-athletic populations is unknown. Our study evaluated the effects of CS on exercise performance and recovery from a graded maximal treadmill test. Insufficiently active adults (n = 10, 60% female, average physical activity ~60 minutes/week) performed two graded maximal exercise tests; one while wearing below-knee CS, and the other trial with regular socks (CON). Order of trials was randomized. For both trials, heart rate, lactate, and rating of perceived exertion were measured at each stage and at one, five, and ten-minutes post-exercise. Additionally, recovery variables (soreness, tightness, annoyingness, tenderness, pulling) were measured at 24 and 48 hours post-exercise using a visual analog scale. Paired-samples t-tests were used to compare exercise and recovery variables between CS and CON trials. Heart rate, lactate, and rating of perceived exertion were not different between trials for any stage during the exercise test or immediate recovery. Most 24-and 48-hour recovery variables were significantly improved after the CS trial, with values 34.6 - 42.3% lower at 24 hours and 40.3 - 61.4% lower at 48 hours compared to CON. Compression socks provided a significant and meaningful improvement in recovery variables 24-48 hours following maximal exercise. Therefore, CS may remove a common barrier to exercise adherence and facilitate more effective training recovery for insufficiently active adults.


Outbreak investigation of ceftriaxone-resistant Salmonella enterica serotype Typhi and its risk factors among the general population in Hyderabad, Pakistan: a matched case-control study.
Pakistan is currently facing the largest outbreak of ceftriaxone-resistant Salmonella enterica serotype Typhi described to date. Here we aimed to report the outbreak investigation done in Hyderabad, Pakistan, and identify disease risk factors. We did an age-matched case-control (1:4) study, in which cases of ceftriaxone-resistant S Typhi were identified from active sentinal sites (three hospitals in Hyderabad, Pakistan), community, and laboratory-based surveillance. Ceftriaxone-resistant S Typhi infection (ie, resistance to ampicillin, chloramphenicol, co-trimoxazole, fluoroquinole, and ceftriaxone) was confirmed using blood culture. Healthy participants (controls) were enrolled for the first 200 people (cases) with ceftriaxone-resistant S Typhi. A structured questionnaire was administered to identify exposures 4 weeks before the illness (cases) or enrolment (controls). Cases were included if written informed consent was provided. Four controls were selected from the same community as the corresponding case, matched on age, being healthy at the time of enrolment, and with no febrile illness in the 4 weeks before enrolment. Samples of drinking water from households and community water sources (ie, hand pumps or taps in common areas outside households) were collected for testing. Conditional logistic regression analysis was used to assess the risk factors for ceftriaxone-resistant S Typhi outbreak in Hyderabad. Between Nov 30, 2016, and Dec 30, 2017, 486 people with ceftriaxone-resistant S Typhi were identified from Hyderabad. Of the 486 cases, 296 (61%) were male and 447 (92%) were aged 15 years or younger. Several factors were significantly associated with acquisition of ceftriaxone-resistant S Typhi, including male sex (adjusted odds ratio [aOR] 1·53, 95% CI 1·06-2·21), eating outside of the house (aOR 1·48, 1·01-2·19), exposure to a patient with S Typhi infection (aOR 3·81, 2·21-6·83), and a history of antimicrobial use (aOR 4·25, 2·53-7·13). Nine (69%) of 13 water samples taken from the households of people with ceftriaxone-resistant S Typhi infection were positive for Escherichia coli, indicating faecal contamination. S Typhi DNA was detected in 12 (22%) of 55 water samples from community water sources. Geospatial mapping showed clustering of cases around sewerage lines. Hyderabad faces the largest reported outbreak of ceftriaxone-resistant S Typhi. The outbreak is suspected to be attributed to the contaminated drinking water, especially the mixing of sewage with drinking water. The risk of ceftriaxone-resistant S Typhi infection is increased among children aged 15 years and younger, male individuals, and those eating outside the house. Vaccination and chlorination of water are recommended for the containment of the outbreak. None.


Fecal genotyping and contaminant analyses reveal variation in individual river otter exposure to localized persistent contaminants.
The present study investigated polyhalogenated aromatic hydrocarbon (PHAH) concentrations in feces of known river otters (Lontra canadensis) along the coast of southern Vancouver Island, British Columbia, Canada. Specifically, we combined microsatellite genotyping of DNA from feces for individual identification with fecal contaminant analyses to evaluate exposure of 23 wild otters to organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), and polybrominated diphenylethers (PBDEs). Overall, feces collected from otters in urban/industrial Victoria Harbor had the greatest concentrations of nearly all compounds assessed. Fecal concentrations of OCPs and PBDEs were generally low throughout the region, whereas PCBs dominated in all locations. Re-sampling of known otters over space and time revealed that PCB exposure varied with movement and landscape use. Otters with the highest fecal PCB concentrations were those inhabiting the inner reaches of Victoria Harbor and adjacent Esquimalt Harbor, and those venturing into the harbor systems. Over 50% of samples collected from eight known otters in Victoria Harbor had total-PCB concentrations above the maximum allowable concentration as established for Eurasian otter (Lutra lutra) feces, with a geometric mean value (10.6 mg/kg lipid wt) that exceeded the reproductive toxicity threshold (9 mg/kg lipid wt). Those results are consistent with our findings from 1998 and 2004, and indicate that the harbors of southern Vancouver Island, particularly Victoria Harbor, are a chronic source of PCB exposure for otters. The present study further demonstrates the suitability of using otter feces as a noninvasive/destructive biomonitoring tool in contaminant studies, particularly when sampling of the same individuals at the local population-level is desired.


Antimicrobial peptides play a functional role in bumblebee anti-trypanosome defense.
Bumblebees, amongst the most important of pollinators, are under enormous population pressures. One of these is disease. The bumblebee and its gut trypanosome Crithidia bombi are one of the fundamental models of ecological immunology. Although there is previous evidence of increased immune gene expression upon Crithidia infection, recent work has focussed on the bumblebee's gut microbiota. Here, by knocking down gene expression using RNAi, we show for the first time that antimicrobial peptides (AMPs) have a functional role in anti-Crithidia defense.


Sex allocation and population structure in apicomplexan (protozoa) parasites.
Establishing the selfing, rate of parasites is important for studies in clinical and epidemiological medicine as well as evolutionary biology Sex allocation theory offers a relatively cheap and easy way to estimate selfing rates in natural parasite populations. Local mate competition (LMC) theory predicts that the optimal sex ratio (r*; defined as proportion males) is related to the selfing rate (s) by the equation r* = (1-s)/2. In this paper, we generalize the application of sex allocation theory across parasitic protozoa in the phylum Apicomplexa. This cosmopolitan phylum consists entirely of parasites, and includes a number of species of medical and veterinary importance. We suggest that LMC theory should apply to eimeriorin intestinal parasites. As predicted, data from 13 eimeriorin species showed a female-biased sex ratio, with the sex ratios suggesting high levels of selfing (0.8-1.0). Importantly, our estimate of the selfing rate in one of these species, Toxoplasma gondii, is in agreement with previous genetic analyses. In contrast, we predict that LMC theory will not apply to the groups in which syzygy occurs (adeleorins, gregarines and piroplasms). Syzygy occurs when a single male gametocyte and a single female gametocyte pair together physically or in close proximity, just prior to fertilization. As predicted, data from four adeleorin species showed sex ratios not significantly different from 0.5.


Recurrence after cure in cranial dural arteriovenous fistulas: a collaborative effort by the Consortium for Dural Arteriovenous Fistula Outcomes Research (CONDOR).
Cranial dural arteriovenous fistulas (dAVFs) are often treated with endovascular therapy, but occasionally a multimodality approach including surgery and/or radiosurgery is utilized. Recurrence after an initial angiographic cure has been reported, with estimated rates ranging from 2% to 14.3%, but few risk factors have been identified. The objective of this study was to identify risk factors associated with recurrence of dAVF after putative cure. The Consortium for Dural Arteriovenous Fistula Outcomes Research (CONDOR) data were retrospectively reviewed. All patients with angiographic cure after treatment and subsequent angiographic follow-up were included. The primary outcome was recurrence, with risk factor analysis. Secondary outcomes included clinical outcomes, morbidity, and mortality associated with recurrence. Risk factor analysis was performed comparing the group of patients who experienced recurrence with those with durable cure (regardless of multiple recurrences). Time-to-event analysis was performed using all collective recurrence events (multiple per patients in some cases). Of the 1077 patients included in the primary CONDOR data set, 457 met inclusion criteria. A total of 32 patients (7%) experienced 34 events of recurrence at a mean of 368.7 days (median 192 days). The recurrence rate was 4.5% overall. Kaplan-Meier analysis predicted long-term recurrence rates approaching 11% at 3 years. Grade III dAVFs treated with endovascular therapy were statistically significantly more likely to experience recurrence than those treated surgically (13.3% vs 0%, p = 0.0001). Tentorial location, cortical venous drainage, and deep cerebral venous drainage were all risk factors for recurrence. Endovascular intervention and radiosurgery were associated with recurrence. Six recurrences were symptomatic, including 2 with hemorrhage, 3 with nonhemorrhagic neurological deficit, and 1 with progressive flow-related symptoms (decreased vision). Recurrence of dAVFs after putative cure can occur after endovascular treatment. Risk factors include tentorial location, cortical venous drainage, and deep cerebral drainage. Multimodality therapy can be used to achieve cure after recurrence. A delayed long-term angiographic evaluation (at least 1 year from cure) may be warranted, especially in cases with risk factors for recurrence.


Familial epilepsy and developmental dysphasia: description of an Italian pedigree with autosomal dominant inheritance and screening of candidate loci.
To describe a familial epileptic condition combining a peculiar electro-clinical pattern with developmental language dysfunction in a large Italian kindred. We studied the clinical and neurophysiological features of a 4-generation family with 10 affected members (3 deceased). We also analysed in 7 affected and 7 healthy members microsatellite markers for 51 candidate loci for epilepsy, including 42 loci containing ion channel genes expressed in the brain, as well as the SPCH1 and SRPX2 loci. Five of the seven living affected members (aged 20-58 years) had the full phenotype (seizures, EEG epileptiform abnormalities and dysphasia). The language dysfunction was the first symptom, becoming evident since the period of language development and mainly consisting of phonemic and syntactic paraphasias, difficulty of expression and reduced verbal fluency. The seizures had their onset between 2 and 23 years and were reported as epileptic falls (4) associated or not with myoclonic features, absences (3), tonic-clonic (1) and complex partial seizures (1). The seizures were easily controlled by antiepileptic treatment in all patients except one. In the five patients with a good response of seizures to treatment, the EEG tracings showed the coexistence of focal and generalized epileptiform abnormalities; in the refractory patient the interictal EEG demonstrated bilateral asynchronous fronto-temporal paroxysms with left predominance and ictal SEEG recording suggested a multifocal origin of the discharges. MRI of the brain was normal in all patients. Linkage analysis provided negative LOD scores for all the investigated loci. We have described a novel familial pattern of epilepsy and developmental dysphasia which is not genetically linked to epilepsy or speech disorder loci, as documented by a candidate-gene linkage approach.


Metaphor and music emotion: Ancient views and future directions.
Music is often described in terms of emotion. This notion is supported by empirical evidence showing that engaging with music is associated with subjective feelings, and with objectively measurable responses at the behavioural, physiological, and neural level. Some accounts, however, reject the idea that music may directly induce emotions. For example, the 'paradox of negative emotion', whereby music described in negative terms is experienced as enjoyable, suggests that music might move the listener through indirect mechanisms in which the emotional experience elicited by music does not always coincide with the emotional label attributed to it. Here we discuss the role of metaphor as a potential mediator in these mechanisms. Drawing on musicological, philosophical, and neuroscientific literature, we suggest that metaphor acts at key stages along and between physical, biological, cognitive, and contextual processes, and propose a model of music experience in which metaphor mediates between language, emotion, and aesthetic response.


Multimode fiber-coupled superconducting nanowire single-photon detector with 70% system efficiency at visible wavelength.
We report the development of the multimode fiber-coupled superconducting nanowire single-photon detector with high system detection efficiency at visible wavelength. The detector consists of a 10.5-nm-thick and 150-nm-wide NbN nanowire meander fabricated on a Si substrate with a multilayer dielectric mirror and a quarter wavelength cavity for obtaining high optical absorptance. The meander area was 35 µm in diameter and coupled with the GRIN-lensed multimode optical fiber with a core diameter of 50 µm. The system reached detection efficiency of 70% with dark count rate of 100 Hz at the wavelength of 635 nm, 3 dB roll-off response counting rate of 8.5 Mcps, and timing jitter of 76 ps.


Reaction-diffusion model as a framework for understanding biological pattern formation.
The Turing, or reaction-diffusion (RD), model is one of the best-known theoretical models used to explain self-regulated pattern formation in the developing animal embryo. Although its real-world relevance was long debated, a number of compelling examples have gradually alleviated much of the skepticism surrounding the model. The RD model can generate a wide variety of spatial patterns, and mathematical studies have revealed the kinds of interactions required for each, giving this model the potential for application as an experimental working hypothesis in a wide variety of morphological phenomena. In this review, we describe the essence of this theory for experimental biologists unfamiliar with the model, using examples from experimental studies in which the RD model is effectively incorporated.


Burden analysis of rare microdeletions suggests a strong impact of neurodevelopmental genes in genetic generalised epilepsies.
Genetic generalised epilepsy (GGE) is the most common form of genetic epilepsy, accounting for 20% of all epilepsies. Genomic copy number variations (CNVs) constitute important genetic risk factors of common GGE syndromes. In our present genome-wide burden analysis, large (≥ 400 kb) and rare (< 1%) autosomal microdeletions with high calling confidence (≥ 200 markers) were assessed by the Affymetrix SNP 6.0 array in European case-control cohorts of 1,366 GGE patients and 5,234 ancestry-matched controls. We aimed to: 1) assess the microdeletion burden in common GGE syndromes, 2) estimate the relative contribution of recurrent microdeletions at genomic rearrangement hotspots and non-recurrent microdeletions, and 3) identify potential candidate genes for GGE. We found a significant excess of microdeletions in 7.3% of GGE patients compared to 4.0% in controls (P = 1.8 x 10-7; OR = 1.9). Recurrent microdeletions at seven known genomic hotspots accounted for 36.9% of all microdeletions identified in the GGE cohort and showed a 7.5-fold increased burden (P = 2.6 x 10-17) relative to controls. Microdeletions affecting either a gene previously implicated in neurodevelopmental disorders (P = 8.0 x 10-18, OR = 4.6) or an evolutionarily conserved brain-expressed gene related to autism spectrum disorder (P = 1.3 x 10-12, OR = 4.1) were significantly enriched in the GGE patients. Microdeletions found only in GGE patients harboured a high proportion of genes previously associated with epilepsy and neuropsychiatric disorders (NRXN1, RBFOX1, PCDH7, KCNA2, EPM2A, RORB, PLCB1). Our results demonstrate that the significantly increased burden of large and rare microdeletions in GGE patients is largely confined to recurrent hotspot microdeletions and microdeletions affecting neurodevelopmental genes, suggesting a strong impact of fundamental neurodevelopmental processes in the pathogenesis of common GGE syndromes.


Prolactin expression in the sheep brain.
Accumulating evidence in rodents suggests that a prolactin locally synthesized and released within the brain can act together with that taken up from the circulation to modulate neuroendocrine responses. The present study was designed to identify the regional patterns of prolactin expression in the adult and developing sheep brain. Specifically, we tested the hypothesis that prolactin is expressed in regions of the adult and fetal sheep brain that are critical in the development of neuroendocrine homeostatic and behavioral functions. The expression of prolactin protein in sheep brain was demonstrated by Western blot analysis and brain prolactin mRNA was detected and sequenced using RT-PCR. In situ hybridization histochemistry revealed that prolactin mRNA was expressed in the medial preoptic area, periventricular preoptic nucleus, bed nucleus of the stria terminalis, and in the paraventricular nucleus of the hypothalamus, particularly the ventral region. The neuroanatomical distribution of prolactin mRNA was best visualized in the fetus and prolactin-immunoreactive neurons could also be identified in late gestation fetuses. Brain prolactin mRNA was expressed as early as day 60 of gestation and increased as the fetus aged and peaked at day 135 (term = 147 days). Prolactin mRNA expression did not exhibit a sex difference in the preoptic area, but in the amygdala prolactin mRNA was significantly higher in females than in males at day 100 of gestation. We conclude that prolactin expressed in adult and fetal sheep brain could be involved in neurodevelopment and/or modulation of the neuroendocrine stress axis, although it is too early to rule out other possibilities given the diverse actions that have been attributed to prolactin.


Towards the genetic basis of cerebral venous thrombosis-the BEAST Consortium: a study protocol.
Cerebral venous thrombosis (CVT) is a rare cerebrovascular condition accounting for <1% of all stroke cases and mainly affects young adults. Its genetic aetiology is not clearly elucidated. To better understand the genetic basis of CVT, we have established an international biobank of CVT cases, Biorepository to Establish the Aetiology of Sinovenous Thrombosis (BEAST) which aims to recruit highly phenotyped cases initially of European descent and later from other populations. To date we have recruited 745 CVT cases from 12 research centres. As an initial step, the consortium plans to undertake a genome-wide association analysis of CVT using the Illumina Infinium HumanCoreExome BeadChip to assess the association and impact of common and low-frequency genetic variants on CVT risk by using a case-control study design. Replication will be performed to confirm putative findings. Furthermore, we aim to identify interactions of genetic variants with several environmental and comorbidity factors which will likely contribute to improve the understanding of the biological mechanisms underlying this complex disease. BEAST meets all ethical standards set by local institutional review boards for each of the participating sites. The research outcomes will be published in international peer-reviewed open-access journals with high impact and visibility. The results will be presented at national and international meetings to highlight the contributions into improving the understanding of the mechanisms underlying this uncommon but important disease. This international DNA repository will become an important resource for investigators in the field of haematological and vascular disorders.


DNA sequence analysis of newly formed telomeres in yeast.
A plasmid can be maintained in linear form in baker's yeast if it bears telomeric sequences at each end. Linear plasmids bearing cloned telomeric C4A4 repeats at one end (test end) and a natural DNA terminus with approximately 300 bps of C4A2 repeats at the other or control end were introduced by transformation into yeast. Test-end termini of 28 to 112 bps supported telomere formation. During telomere formation, C4A2 repeats were often transferred to test-end termini. To determine in greater detail the fate of test-end sequences on these plasmids after propagation in yeast, test-end telomeres were subcloned into E. coli and sequenced. DNA sequencing established a number of points about the molecular events involved in telomere formation in yeast. The results suggest that there are at least two mechanisms for telomere formation in yeast. One is mediated by a recombination event that requires neither a long stretch of homology nor the RAD52 gene product. The other mechanism is by addition of C1-3A repeats to the termini of linear DNA molecules. The telomeric sequence required to support C1-3A addition need not be at the very end of a molecule for telomere formation.


Validation of a Tibetan translation of the Hopkins Symptom Checklist 25 and the Harvard Trauma Questionnaire.
This study sought to translate and validate the Hopkins Symptom Checklist-25 (HSCL) and the Harvard Trauma Questionnaire (HTQ) in a Tibetan population. Translated questionnaires were administered to 57 Tibetan survivors of torture/human rights abuses living in the United States and receiving services in a torture treatment program. Participants were evaluated to determine if they met criteria for major depressive episode, generalized anxiety disorder, or posttraumatic stress disorder (PTSD). Coefficient alpha for the HSCL Anxiety subscale (.89), Depression subscale (.92), and the HTQ (.89) were high. Diagnostic accuracy using receiver operating characteristic curve analysis generated good classification accuracy for anxiety (.89), depression (.92), and PTSD (.83). However, although sensitivity and specificity for HSCL subscales were quite high, the HTQ generated low sensitivity (.33), partly because of a low rate of PTSD. Results support the reliability and validity of the HSCL but suggest further study of the HTQ with this population is required.


PiUS (Pi uptake stimulator) is an inositol hexakisphosphate kinase.
A cDNA cloned from its ability to stimulate inorganic phosphate uptake in Xenopus oocytes (phosphate uptake stimulator (PiUS)) shows significant similarity with inositol 1,4,5-trisphosphate 3-kinase. However, the expressed PiUS protein showed no detectable activity against inositol 1,4,5-trisphosphate, nor the 1,3,4,5- or 3,4,5, 6-isomers of inositol tetrakisphosphate, whereas it was very active in converting inositol hexakisphosphate (InsP(6)) to inositol heptakisphosphate (InsP(7)). PiUS is a member of a family of enzymes found in many eukaryotes and we discuss the implications of this for the functions of InsP(7) and for the evolution of inositol phosphate kinases.


A comparison of antinociception induced by foot shock and morphine.
We compared the antinociception produced by brief intermittent foot shock (0.8-1.0 mA for 20 sec) and morphine by measuring the peak and duration of the effect, the consequences of spinalectomy and the sensitivity to antagonism by naloxone and d- and l-pentazocine and cyclazocine. Foot shock produced a peak antinociception (FSIA) equal to 10 mg/kg of morphine but the duration of FSIA was much shorter. Naloxone antagonized FSIA but a much larger dose (10 mg/kg) was required than for antagonism of morphine. The d-isomers of pentazocine and cyclazocine reduced FSIA but had no effect on morphine antinociception, whereas the l-isomers increased the peak and duration of FSIA and antagonized morphine-induced antinociception. Spinalectomy, which is known to block morphine antinociception, also blocks FSIA. Foot-shock stress did not produce an increase in tail-flick latency in morphine or methadone-tolerant animals demonstrating cross-tolerance between FSIA and morphine and methadone. The similarities between FSIA and morphine-induced antinociception suggest that similar opioid systems may be involved in both. However, the differences suggest that antinociception produced by brief FSIA involves a nonopiate as well as an opiate mechanism, perhaps with multiple opioid receptor sites having different affinities for the isomers of the antagonists.


Two novel QTLs regulate internode elongation in deepwater rice during the early vegetative stage.
Deepwater rice possesses internode elongation ability to avoid drowning under deepwater conditions. Previous studies identified three QTLs regulating internode elongation ability on chromosomes 1, 3 and 12 using different populations. However, these QTLs only induce internode elongation in response to deepwater conditions from the 7-leaf stage and not during the early leaf stage. In this study, we detected two novel QTLs, qTIL2 and qTIL4 regulating deepwater response at the early leaf stage using an F(2) population derived from the cross between NIL1-3-12 carrying the three QTLs regulating deepwater response in T65 (O. sativa ssp. japonica) genetic background and C9285 (O. sativa ssp. indica, deepwater rice). Plants of the BC(2)F(2) population derived from NIL1-3-12/C9285 and the RILs of T65/Bhadua (O. sativa ssp. indica, deepwater rice) possessing these QTLs as well as the three QTLs previously identified also showed internode elongation during the early leaf stage. These results indicate that qTIL2 and qTIL4 regulate early internode elongation and function in coordination with the three major QTLs under deepwater conditions. The results presented here would not only help define the mechanism of deepwater response in rice but also contribute in the breeding of deepwater tolerant rice that is adapted to various water depths.


Small-diameter TIPS combined with splenic artery embolization in the management of refractory ascites in cirrhotic patients.
Maximally decreasing portal pressures with transjugular intrahepatic portosystemic shunt (TIPS) is associated with improved ascites control but also increased encephalopathy incidence. Since splenic venous flow contributes to portal hypertension, we assessed if combining small-diameter TIPS with splenic artery embolization could improve ascites while minimizing encephalopathy. Fifty-five patients underwent TIPS creation for refractory ascites. Subjects underwent creation of 8 mm TIPS followed by proximal splenic artery embolization (group A, n=8), or of 8 mm (group B, n=6) or 10 mm TIPS (group C, n=41) without splenic embolization. Data were retrospectively reviewed. In group A, median portosystemic gradient decreased from 19 mmHg to 9 mmHg after TIPS, and 8 mmHg after subsequent splenic artery embolization. In groups B and C, gradient decreased from 15 mmHg to 8 mmHg and 16 mmHg to 6 mmHg. All patients except for one in group A and two in C had greater than 50% reduction in the number of paracenteses in 3 months. Any postprocedural encephalopathy incidence was 62%, 50%, 83% in groups A, B, and C, respectively. Overall, 20% of subjects with 10 mm TIPS required TIPS reduction/closure compared to 7% of subjects with 8 mm TIPS. We found that 8 mm diameter TIPS provided similar ascites control compared to 10 mm TIPS regardless of splenic embolization. While more patients with 10 mm TIPS required reduction/closure for severe encephalopathy, the study was underpowered for definitive assessment. Splenic embolization might have the potential to further decrease portosystemic gradient and ascites as an alternative to dilation of TIPS to 10 mm minimizing the risk of encephalopathy, but larger studies are warranted.


Pathophysiological and diagnostic implications of cardiac biomarkers and antidiuretic hormone release in distinguishing immersion pulmonary edema from decompression sickness.
Immersion pulmonary edema (IPE) is a misdiagnosed environmental illness caused by water immersion, cold, and exertion. IPE occurs typically during SCUBA diving, snorkeling, and swimming. IPE is sometimes associated with myocardial injury and/or loss of consciousness in water, which may be fatal. IPE is thought to involve hemodynamic and cardiovascular disturbances, but its pathophysiology remains largely unclear, which makes IPE prevention difficult. This observational study aimed to document IPE pathogenesis and improve diagnostic reliability, including distinguishing in some conditions IPE from decompression sickness (DCS), another diving-related disorder.Thirty-one patients (19 IPE, 12 DCS) treated at the Hyperbaric Medicine Department (Ste-Anne hospital, Toulon, France; July 2013-June 2014) were recruited into the study. Ten healthy divers were recruited as controls. We tested: (i) copeptin, a surrogate marker for antidiuretic hormone and a stress marker; (ii) ischemia-modified albumin, an ischemia/hypoxia marker; (iii) brain-natriuretic peptide (BNP), a marker of heart failure, and (iv) ultrasensitive-cardiac troponin-I (cTnI), a marker of myocardial ischemia.We found that copeptin and cardiac biomarkers were higher in IPE versus DCS and controls: (i) copeptin: 68% of IPE patients had a high level versus 25% of DCS patients (P < 0.05) (mean ± standard-deviation: IPE: 53 ± 61 pmol/L; DCS: 15 ± 17; controls: 6 ± 3; IPE versus DCS or controls: P < 0.05); (ii) ischemia-modified albumin: 68% of IPE patients had a high level versus 16% of DCS patients (P < 0.05) (IPE: 123 ± 25 arbitrary-units; DCS: 84 ± 25; controls: 94 ± 7; IPE versus DCS or controls: P < 0.05); (iii) BNP: 53% of IPE patients had a high level, DCS patients having normal values (P < 0.05) (IPE: 383 ± 394 ng/L; DCS: 37 ± 28; controls: 19 ± 15; IPE versus DCS or controls: P < 0.01); (iv) cTnI: 63% of IPE patients had a high level, DCS patients having normal values (P < 0.05) (IPE: 0.66 ± 1.50 μg/L; DCS: 0.0061 ± 0.0040; controls: 0.0090 ± 0.01; IPE versus DCS or controls: P < 0.01). The combined "BNP-cTnI" levels provided most discrimination: all IPE patients, but none of the DCS patients, had elevated levels of either/both of these markers.We propose that antidiuretic hormone acts together with a myocardial ischemic process to promote IPE. Thus, monitoring of antidiuretic hormone and cardiac biomarkers can help to make a quick and reliable diagnosis of IPE.


Who is in the sample? An analysis of real and surrogate users as participants in user study research in the information technology fields.
Constructing a sample of real users as participants in user studies is considered by most researchers to be vital for the validity, usefulness, and applicability of research findings. However, how often user studies reported in information technology academic literature sample real users or surrogate users is unknown. Therefore, it is uncertain whether or not the use of surrogate users in place of real users is a widespread problem within user study practice. To determine how often user studies reported in peer-reviewed information technology literature sample real users or surrogate users as participants. We analyzed 725 user studies reported in 628 peer-reviewed articles published from 2013 through 2021 in 233 unique conference and journal outlets, retrieved from the ACM Digital Library, IEEE Xplore, and Web of Science archives. To study the sample selection choices, we categorized each study as generic (i.e., users are from the general population) or targeted (i.e., users are from a specific subpopulation), and the sampled study participants as real users (i.e., from the study population) or surrogate users (i.e., other than real users). Our analysis of all 725 user studies shows that roughly two-thirds (75.4%) sampled real users. However, of the targeted studies, only around half (58.4%) sampled real users. Of the targeted studies sampling surrogate users, the majority (69.7%) used students, around one-in-four (23.6%) sampled through crowdsourcing, and the remaining 6.7% of studies used researchers or did not specify who the participants were. Key findings are as follows: (a) the state of sampling real users in information technology research has substantial room for improvement for targeted studies; (b) researchers often do not explicitly characterize their study participants in adequate detail, which is probably the most disconcerting finding; and (c) suggestions are provided for recruiting real users, which may be challenging for researchers. The results imply a need for standard guidelines for reporting the types of users sampled for a user study. We provide a template for reporting user study sampling with examples.


Affirmative action in medical education and its effect on Howard and Meharry: a study of the class of 1975.
During the decade of the 1970s, affirmative action programs were introduced in US medical schools for the purpose of increasing the number of black and other minority medical students and of improving the medical care resources for black and other minority communities. Having for many years served as the main sources of black physicians in the US, Howard University College of Medicine and Meharry Medical College School of Medicine were also affected by affirmative action. No previous studies have compared the black graduates from Howard and Meharry with black and other minority graduates from the other US medical schools.The purpose of this study was to compare these medical school graduates in terms of actual choice of specialty, patient characteristics, practice location, and specialty board certification, using the graduating class of 1975. A greater proportion of black graduates from Howard and Meharry chose primary care specialties than did black graduates from other schools, though this difference was not statistically significant. Black graduates from Howard and Meharry had significantly greater proportions of black patients compared with black graduates from other schools, but the same proportion of Medicaid patients.Though not statistically significant, black graduates from Howard and Meharry were less likely to be found practicing in federally designated underserved areas. Black graduates from Meharry were significantly less likely to have achieved specialty board certification, compared with graduates from Howard or the other medical schools. These results illustrate the experience of Howard and Meharry during the era of affirmative action and generally support their critically important role in producing black physicians and enhancing medical care resources in the black community.


RNA-Catalyzed CoA, NAD, and FAD synthesis from phosphopantetheine, NMN, and FMN.
A novel in vitro selection method was developed to isolate RNA sequences with coenzyme-synthesizing activities. We used size-heterogeneous libraries containing randomized ribonucleotide sequences of four different lengths (30N, 60N, 100N, and 140N), all with 5'-ATP initiation. Two RNAs, CoES7 (30N) and CoES21 (60N), are able to catalyze the synthesis of three common coenzymes, CoA, NAD, and FAD, from their precursors, 4'-phosphopantetheine, NMN, and FMN, respectively. Both ribozymes require divalent manganese for activities. The results support the availability of these coenzymes in an RNA world, and point to a chemical explanation for the complex bipartite structures of many coenzymes.


Community-based surveillance of maternal deaths in rural Ghana.
To examine the feasibility and effectiveness of community-based maternal mortality surveillance in rural Ghana, where most information on maternal deaths usually comes from retrospective surveys and hospital records. In 2013, community-based surveillance volunteers used a modified reproductive age mortality survey (RAMOS 4+2) to interview family members of women of reproductive age (13-49 years) who died in Bosomtwe district in the previous five years. The survey comprised four yes-no questions and two supplementary questions. Verbal autopsies were done if there was a positive answer to at least one yes-no question. A mortality review committee established the cause of death. Survey results were available for 357 women of reproductive age who died in the district. A positive response to at least one yes-no question was recorded for respondents reporting on the deaths of 132 women. These women had either a maternal death or died within one year of termination of pregnancy. Review of 108 available verbal autopsies found that 64 women had a maternal or late maternal death and 36 died of causes unrelated to childbearing. The most common causes of death were haemorrhage (15) and abortion (14). The resulting maternal mortality ratio was 357 per 100 000 live births, compared with 128 per 100 000 live births derived from hospital records. The community-based mortality survey was effective for ascertaining maternal deaths and identified many deaths not included in hospital records. National surveys could provide the information needed to end preventable maternal mortality by 2030.


Structural variations within the transferrin binding site on transferrin-binding protein B, TbpB.
Pathogenic bacteria acquire the essential element iron through specialized uptake pathways that are necessary in the iron-limiting environments of the host. Members of the Gram-negative Neisseriaceae and Pasteurellaceae families have adapted to acquire iron from the host iron binding glycoprotein, transferrin (Tf), through a receptor complex comprised of transferring-binding protein (Tbp) A and B. Because of the critical role they play in the host, these surface-exposed proteins are invariably present in clinical isolates and thus are considered prime vaccine targets. The specific interactions between TbpB and Tf are essential and ultimately might be exploited to create a broad-spectrum vaccine. In this study, we report the structure of TbpBs from two porcine pathogens, Actinobacillus pleuropneumoniae and suis. Paradoxically, despite a common Tf target, these swine related TbpBs show substantial sequence variation in their Tf-binding site. The TbpB structures, supported by docking simulations, surface plasmon resonance and hydrogen/deuterium exchange experiments with wild-type and mutant TbpBs, explain why there are structurally conserved elements within TbpB homologs despite major sequence variation that are required for binding Tf.


The effect of nutrition intervention in lung cancer patients undergoing chemotherapy and/or radiotherapy: a systematic review.
The prevalence of malnutrition in lung cancer patients across a variety of treatment modalities and disease stages ranges from 45% to 69%. Malnutrition is associated with poorer clinical outcomes in cancer patients. This systematic review examined whether dietary counseling or oral supplements during chemotherapy and/or radiotherapy in patients with lung cancer affect patient or clinical outcomes. Relevant nutrition intervention studies from 1980 to March 2012 were identified. Articles meeting predetermined inclusion/exclusion criteria were critically appraised and included in the review. The outcomes of interest included dietary intake, weight, nutritional status, quality of life, functional status, treatment response, and survival. Five eligible studies were identified including 3 randomized controlled trials, 1 historical cohort, and 1 case series. These studies suggest dietary counseling improves energy and protein intake during chemotherapy in patients with lung cancer but has no benefit to other outcomes during chemotherapy. There is insufficient evidence regarding the effect on patient or clinical outcomes during radiotherapy. Randomized trials examining dietary counseling in patients with lung cancer during radiotherapy are required.


Proton pump inhibitors: perspectives of patients and their GPs.
There is growing concern with the rapid increase in prescribing proton pump inhibitor drugs (PPIs) for a variety of gastrointestinal disorders, and the escalating costs associated with this trend. Explanations have included that general practitioners (GPs) prescribe PPIs inappropriately and that patients demand PPIs and use them as a way of avoiding having to make lifestyle changes. To compare the perspectives of GPs and their patients on the need for PPIs, to examine the pressure to prescribe, and to examine the effect of PPIs on lifestyle. Qualitative comparative study based on semi-structured interviews. Twenty-six GPs in seven practices in the West Midlands and 82 of their patients on repeat prescriptions for PPIs. Interviews were conducted covering a wide range of topics, including: experience, cause, course, and outcome of stomach problems; effectiveness of PPIs; and role of lifestyle in controlling symptoms. The transcripts were studied repeatedly to look for the occurrence and distribution of material relating to these issues, as well as other responder-driven issues. Codebooks were devised to enable a simple categorisation and systematic comparison of cases. GPs and patients agreed about the severity and unpleasantness of stomach symptoms for which PPIs were prescribed. While GPs and patients regarded PPIs as a very effective treatment, GPs rated their efficacy more highly than patients. Half of the GP interviews reproduced the stereotype of the demanding patient and of patients using PPIs to support unhealthy lifestyles. There was little evidence from patient interviews to support either stereotype. Doctors underestimated patient concerns about side-effects, safety, and long-term use of PPIs, and the willingness of patients to achieve the minimum effective dose by experimenting with their treatment. GPs felt that the pressure to prescribe PPIs was outweighed by the pressure not to prescribe, and most GPs had responded to the call to cut the prescribing of PPIs. Different strategies were employed to cut prescribing, including the wholesale switching of patients on a treatment dose of one brand of PPI to a maintenance dose of a cheaper brand of PPI, known as 'double switching'. The stereotypes of 'profligate prescriber', 'demanding patient', and 'adverse lifestyle', as explanations for the increase in the prescribing of PPIs, were not upheld. The stereotype of patients demanding PPIs may arise from GPs' internal pressure to prescribe being externalised onto patients. The extent to which health behaviour contributes to gastric disorders needs to be established empirically. Labelling PPI patients as having a poor lifestyle may be used as a means of reducing legitimate need for PPIs. Current policy relating to switching of dose and brand of PPI should be reviewed.


Guanine nucleotide-binding proteins modulate desmethoxyverapamil binding to calcium channels in vascular smooth muscle.
Specific binding of the Ca++ antagonist desmethoxyverapamil, (-)-[3H]D888, to cell membranes of equine portal vein smooth muscle was inhibited in a concentration-dependent manner by guanosine 5'-O-(gamma-thio)triphosphate and ATP but was little affected by guanosine 5'-O-(beta-thio)diphosphate, noradrenaline or phorbol 12-myristate 13-acetate ester. Inhibition constants for GTP and ATP were in the range of 0.1 to 0.3 mM. From Scatchard plots and dissociation kinetic experiments, it is proposed that D888 high affinity binding sites are transferred into low affinity sites. In intact strips of rat portal vein bathed in physiological solution, both noradrenalin and a combination of aluminum chloride and sodium fluoride inhibited (-)-[3H]D888 binding, whereas guanosine 5'-O-(gamma-thio)triphosphate was without effect. In strips pretreated with 1 microM prazosin or 10 micrograms/ml pertussis toxin (PTX) for 6 h, noradrenalin had no effect on specific (-)-[3H]D888 binding. In addition, inhibition of (-)-[3H]D888 binding in the presence of 3 microM noradrenalin was reversed in a concentration-dependent manner by prazosin but not by propranolol. Noradrenalin-induced contractions were inhibited in a concentration-dependent manner by D888. In strips preincubated with 10 micrograms/ml PTX for 6 h, the concentration-response curve was shifted to the left, indicating that removal of the PTX sensitive transduction pathway increased D888 affinity for its specific binding sites. These results show that (-)-[3H]D888 binding to Ca++ channels is changed by GTP analogs in a way that suggests that a PTX-sensitive guanine nucleotide-binding protein may directly interact with Ca++ channels in response to activation of alpha 1 adrenoceptors.


HIV evolution in early infection: selection pressures, patterns of insertion and deletion, and the impact of APOBEC.
The pattern of viral diversification in newly infected individuals provides information about the host environment and immune responses typically experienced by the newly transmitted virus. For example, sites that tend to evolve rapidly across multiple early-infection patients could be involved in enabling escape from common early immune responses, could represent adaptation for rapid growth in a newly infected host, or could represent reversion from less fit forms of the virus that were selected for immune escape in previous hosts. Here we investigated the diversification of HIV-1 env coding sequences in 81 very early B subtype infections previously shown to have resulted from transmission or expansion of single viruses (n = 78) or two closely related viruses (n = 3). In these cases, the sequence of the infecting virus can be estimated accurately, enabling inference of both the direction of substitutions as well as distinction between insertion and deletion events. By integrating information across multiple acutely infected hosts, we find evidence of adaptive evolution of HIV-1 env and identify a subset of codon sites that diversified more rapidly than can be explained by a model of neutral evolution. Of 24 such rapidly diversifying sites, 14 were either i) clustered and embedded in CTL epitopes that were verified experimentally or predicted based on the individual's HLA or ii) in a nucleotide context indicative of APOBEC-mediated G-to-A substitutions, despite having excluded heavily hypermutated sequences prior to the analysis. In several cases, a rapidly evolving site was embedded both in an APOBEC motif and in a CTL epitope, suggesting that APOBEC may facilitate early immune escape. Ten rapidly diversifying sites could not be explained by CTL escape or APOBEC hypermutation, including the most frequently mutated site, in the fusion peptide of gp41. We also examined the distribution, extent, and sequence context of insertions and deletions, and we provide evidence that the length variation seen in hypervariable loop regions of the envelope glycoprotein is a consequence of selection and not of mutational hotspots. Our results provide a detailed view of the process of diversification of HIV-1 following transmission, highlighting the role of CTL escape and hypermutation in shaping viral evolution during the establishment of new infections.